tbuckley/cabot-search huggingface dataset:
MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) and<i>in vivo</i> validation
Authors: Anna Kolodziejczak, Florian Selt, Heike Peterziel, Nora Jamaladdin, Norman Mack, Kendra Maass, Marcel Kool, Christel Herold-Mende, Ahmed El Damaty, Ina Oehme, David T W Jones, Olaf Witt, Kristian W Pajtler, Christian Kratz, Stefan M Pfister, Till Milde
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Disorders with Abnormal DNA Damage Response/Repair (DADDRs) are inherited conditions caused by constitutional mutations of DNA damage response and repair genes and are characterized by an increased cancer risk. Furthermore, affected individuals also show an elevated risk of secondary neoplasms as well as excessive toxicity, poor therapy response and increased mortality when treated with standard radiation and chemotherapy regimens. The main aim of this project is to screen for potential novel chemotherapeutic approaches for these cancer entities, and to employ faithful PDX models for in vivo validation. METHODS: In vitro drug screening was performed using a custom library composed of 345 compounds targeting 61 different proteins. For two specific DADDRs, Li-Fraumeni syndrome (LFS) and Constitutional Mismatch Repair Deficiency (CMMRD), two cancerous (glioblastoma and medulloblastoma) and one non-cancerous cell lines were selected to model each of these conditions. Performance of each drug was assessed based on its efficacy (sensitivity score) and genotoxicity (micronucleus assay). For DADDR PDX model establishment tumor material from DADDR patients is currently being injected orthotopically (brain tumors) or subcutaneously (non-brain tumors) into NSG mice. Following engraftment and expansion, the PDX models will be characterized molecularly and compared with original patient material. RESULTS AND OUTLOOK: In vitro screening revealed n=26 drugs that fulfilled the following criteria: a) favorable toxicity in cancerous cell lines compared to non-cancerous cell lines, b) little to no genotoxic effect in non-cancerous cell lines. These characteristics qualify them as potentially suitable candidates for novel therapeutic approaches specifically for DADDR patients. The hits included inhibitors of ATM/ATR, CHK1/CHK2, DHFR, mTOR and PI3K, as well as microtubule-associated compounds. Combination testing and further validation of these hits using disease-specific in vitro and in vivo PDX models is ongoing.
DIPG-48. MRI volumetric and machine learning based analyses predict survival outcome in pediatric diffuse midline glioma
Authors: Erin R Bonner, Xinyang Liu, Carlos Tor-Diez, Madhuri Kambhampati, Augustine Eze, Roger J Packer, Javad Nazarian, Marius George Linguraru, Miriam Bornhorst
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Diffuse midline glioma (DMG) is a fatal childhood CNS tumor. Magnetic resonance imaging (MRI) is the gold standard for DMG diagnosis and monitoring of response to therapy. Leveraging novel MRI analytical approaches, including volumetric and machine learning based analyses, may aid in the prediction of patient overall survival (OS) and help to identify high-risk cases. METHODS: T1- and T2-weighted MR images were retrospectively collected from children and young adults diagnosed with DMG (n=43). MRI features, including manually determined 3D tumor volume (T2), T1 contrast-enhancing tumor volume, T1 relative to T2 volume (T1/T2), tumor relative to whole brain volume, tumor average intensity, and tumor heterogeneity (i.e., intensity skewness and kurtosis), were evaluated at upfront diagnosis. MRI features were analyzed to identify significant predictors of OS outcome, which was defined as OS shorter, or longer, than one year from diagnosis. A support vector machine was used to predict OS outcomes using combinations of these features. RESULTS: The presence of T1 contrast-enhancing tumor at diagnosis (p=0.01), and a high T1/T2 ratio (&amp;gt;25%, p=0.009), predicted significantly shorter median OS. Moreover, feature selection identified T2 mean intensity (p&amp;lt;0.001), T2 image intensity skew (p=0.006), T1/T2 ratio (p=0.02), and T1 volume relative to whole brain (p=0.03) as significant predictors of OS outcome (short versus long). Combining T2 mean intensity, T2 image skew, T1 segment kurtosis and patient gender resulted in OS outcome prediction accuracy of 83.3% (sensitivity=85%, specificity=81.8%, n=42 cases).CONCLUSION: We have identified MRI volume and imaging features that significantly predict OS outcome in children diagnosed with DMG. Our findings provide a framework for incorporating MRI volumetric and machine learning analyses into the clinical setting, allowing for the customization of treatment based on tumor risk characteristics.
Digital patient-reported outcomes and serological response to SARS-COV-2 vaccines in patients with cancer.
Authors: Jose L. Sandoval, Sebastien Bugeia, Santeri Mentu, Garance Gutknecht, Jussi Ekström, Anna Battagin, Alex Friedlaender, Mari Metso-Lintula, Vesa V Kataja, Pierre-Yves Dietrich, Nicolas Mach, Alfredo Addeo
Journal: Journal of Clinical Oncology (2022)

e13606 Background: SARS-CoV-2 vaccines have changed the course of the current global pandemic. Cancer patients were identified as highrisk of adverse infection outcomes. We have previously characterised the serological response to SARS-CoV-2 vaccines in 220 cancer patients treated at our institution. In addition these patients were given the possibility to report their symptoms (patient-reported outcomes, PROs) weekly using a digital platform (ePROs). We sought to determine if, in cancer patients, the prospectively recorded post-vaccination ePROs could predict the serological response to SARS-CoV-2 vaccines. Methods: We used a pre-existing digital platform that allows monitoring of PROs using weekly questionnaires sent to patients and available on their desktop computers, tablets or smartphones. Serial serologies were performed at 28, 50 and 115 days after vaccination. Results: We observed that at day 50 after the first vaccination dose, coinciding with three weeks after the second dose, patients could be divided into two groups according to their serological response (low – below 1500 U/ml and high – above or equal 1500 U/ml). A peak in symptom burden could be observed after the second dose, as previously described. Omitting ePRO features decreased prediction performance of all models, whereas omitting baseline symptom scores had inconsistent effects. Among all models and feature constructions, the top performance metrics were given by the nearest centroid model 7 with baseline symptoms omitted and 20 features chosen with the aforementioned procedure. The model achieved an accuracy of 0.704, an F1-score of 0.759 and an MCC of 0.398. Conclusions: we were able to identify the patients who achieved higher antibody levels against SARS-COV-2 based on the symptom burden reported through ePROs. This represents the first model showing that symptoms, assessed through ePRO can be predictive of response to vaccines. Our results could also be useful information for patients, as they could assuage their fears about adverse -effects, through the knowledge that toxicity could predict better protection against SARS-COV-2. The same toxicity-based prediction of efficacy has been identified with immunotherapy in cancer and is now a routine part of clinical discussions with patients.
Assessment of Delayed Large Local Reactions After the First Dose of the SARS-CoV-2 mRNA-1273 Vaccine in Japan
Authors: Toshihide Higashino, Yuki Yamazaki, Satoko Senda, Yushi Satou, Yuiko Yonekura, Kazuo Imai, Junko Arakawa, Shuichi Kawano, Hiroshi Horinosono, Yoshinori Miura
Journal: JAMA Dermatology (2022)

A delayed large local reaction (DLLR) is a delayed-onset adverse skin reaction that may occur after injection of the mRNA-1273 vaccine against SARS-CoV-2.To examine the associations between sex and age and susceptibility of DLLRs after mRNA-1273 vaccination.This retrospective cross-sectional study was conducted at the Self-Defense Forces large-scale vaccination center in Tokyo, Japan, from May 24 to November 30, 2021. Participants were recipients of the second dose of the mRNA-1273 vaccine who had received the first dose 4 to 6 weeks earlier. Five experienced dermatologists interviewed participants to assess whether they had experienced symptoms of DLLR after administration of the first dose of the vaccine.Receipt of the first dose of the mRNA-1273 vaccine.The primary outcome was the incidence rate of DLLR stratified by sex and age group. Odds ratios (ORs) were calculated to evaluate the differences between groups. Outcomes were tested for significance using the Pearson χ2 test with 95% CIs.Of 5893 participants in the study, 3318 (56.3%) were male (median age, 55 years [IQR, 38-68 years]) and 2575 (43.7%) were female (median age, 50 years [IQR, 34-67 years]). A total of 747 participants (12.7%) experienced DLLR symptoms after the first dose of the mRNA-1273 vaccine. Symptoms were mild and not considered as contraindications to the vaccine. The incidence rate was significantly higher among females (22.4% [577 participants]; OR, 5.30; 95% CI, 4.42-6.34) than among males (5.1% [170 participants]; reference). Moreover, the incidence rate was significantly higher among participants aged 30 to 39 years (14.3% [129 participants]; OR, 1.68; 95% CI, 1.25-2.26), 40 to 49 years (15.8% [136 participants]; OR, 1.89; 95% CI, 1.41-2.53), 50 to 59 years (14.9% [104 participants]; OR, 1.76; 95% CI, 1.29-2.40), and 60 to 69 years (12.6% [182 participants]; OR, 1.45; 95% CI, 1.10-1.91) than among participants aged 18 to 29 years (9.0% [81 participants]; reference).In this cross-sectional study, the first dose of the SARS-CoV-2 mRNA-1273 vaccine was associated with a higher incidence of DLLR among females and among individuals aged 30 to 69 years. The findings suggest that DLLR may be a type IV allergic skin reaction.
Firmicutes in gut microbiota correlate with blood testosterone levels in elderly men
Authors: K. Fujita, M. Matsushita, D. Motooka, K. Hatano, M. Nishimoto, E. Banno, J. Hata, A. Tsujimura, S. Nakamura, T. Minami, M. Nozawa, K. Yoshimura, W. Obara, H. Uemura, N. Nonomura
Journal: European Urology (2022)
Personalized multimodality therapy with immune checkpoint inhibitors, chemotherapy, and targeted treatment (ICTriplex) in advanced/refractory cancer.
Authors: Philip A. Salem, Khaled W. Jabboury, William G.B. McCallum, Randall A. Stenoien, Thomas M. Wheeler
Journal: Journal of Clinical Oncology (2022)

e14590 Background: Advanced/refractory malignancies are associated with poor prognosis and their treatment remains a major challenge. The combination of immune checkpoint inhibitors (ICI) and chemotherapy (CT) has been shown in some cancers to be superior to chemotherapy alone. In our treatment program (ICTriplex), targeted therapy (TT) was added to this combination for the treatment of these diseases, as these three approaches have convergent efficacy but divergent toxicity. Our initial data was previously reported in ASCO 2019 (abstract e14254) and ASCO 2020 (abstract e15150). Methods: Treatment was highly personalized and was tailored to the individual patient depending on diagnosis, prior therapy, and genomic profiling. Between April 2016 and January 2022, 41 patients with advanced malignancies were treated. The median age was 59 years (range 17-78). 24 patients were female. The Median Eastern Cooperative Oncology Group Performance Status was 2 (range 0-4). Tumor types included; lung (10), pancreas (7), colorectal (4), cholangiocarcinoma (3), breast (3), ovarian (2), Glioblastoma (2), cervical (2), sarcoma (2), melanoma (2), Hodgkin’s (1), gallbladder (1), thymoma (1), and gastric (1). PDL-1 status was positive in 10, negative in 16 and unknown in 15. 32 patients received prior therapy. Of these, 9 received ICI, 14 received TT, and 31 received chemotherapy for a median of 2 regimens (range 1-11). In ICTriplex, the ICIs used were Pembrolizumab in 14, Nivolumab in 12, and Atezolizumab in 7. 8 patients received dual ICI with ipilimumab. Combination chemotherapy including platinum was used in 21 patients, taxanes in 17, and gemcitabine in 24. TT included 18 agents with erlotinib in 9 and bevacizumab in 8. Response was evaluated by both PET/CT and CT scans. A complete response was achieved when all metabolic activity had resolved. Results: A complete response (CR) was achieved in 19 patients (46.3%), and a partial response (PR) in 16 (39%), with a total response rate of 85.3%. All but 2 patients had response. Of the 10 patients with lung cancer, 7 had CR, and 3 of them had a duration of response of more than 30 months. Also, 3 of the complete responders with brain metastases achieved intracranial CR by MRI without radiation. 2 patients with pancreatic cancer had a response duration of more than 30 months. Regarding side effects, 2 patients died of pulmonary complications possibly due to treatment. There were no other unexpected side effects. Conclusions: ICTriplex therapy is highly effective in advanced/refractory cancer and therefore should be considered when standard therapy fails, as well as for patients for whom standard therapy is not available.
Association of High-Volume Centers With Survival Outcomes Among Patients With Nontraumatic Out-of-Hospital Cardiac Arrest
Authors: Amelia Xin Chun Goh, Jie Cong Seow, Melvin Yong Hao Lai, Nan Liu, Yi Man Goh, Marcus Eng Hock Ong, Shir Lynn Lim, Jamie Sin Ying Ho, Jun Wei Yeo, Andrew Fu Wah Ho
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Although high volume of cases of out-of-hospital cardiac arrest (OHCA) is a key feature of cardiac arrest centers, which have proven survival benefit, the role of center volume as an independent variable associated with improved outcomes is unclear. <h3>Objective</h3> To assess the association of high-volume centers with survival and neurological outcomes in nontraumatic OHCA. <h3>Data Sources</h3> Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to October 11, 2021, for studies including adult patients with nontraumatic OHCA who were treated at high-volume vs non–high-volume centers. <h3>Study Selection</h3> Randomized clinical trials, nonrandomized studies of interventions, prospective cohort studies, and retrospective cohort studies were selected that met the following criteria: (1) adult patients with OHCA of nontraumatic etiology, (2) comparison of high-volume with low-volume centers, (3) report of a volume-outcome association, and (4) report of outcomes of interest. At least 2 authors independently reviewed each article, blinded to each other’s decision. <h3>Data Extraction and Synthesis</h3> Data abstraction and quality assessment were independently conducted by 2 authors. Meta-analyses were performed for adjusted odds ratios (aORs) and crude ORs using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. <h3>Main Outcomes and Measures</h3> Survival and good neurological outcomes according to the Cerebral Performance Categories Scale at hospital discharge or 30 days. <h3>Results</h3> A total of 16 studies involving 82 769 patients were included. Five studies defined high volume as 40 or more cases of OHCA per year; 3 studies defined high volume as greater than 100 cases of OHCA per year. All other studies differed in definitions. Survival to discharge or 30 days improved with treatment at high-volume centers, regardless of whether aORs (1.28 [95% CI, 1.00-1.64]) or crude ORs (1.43 [95% CI, 1.09-1.87]) were pooled. There was no association between center volume and good neurological outcomes at 30 days or hospital discharge in patients with OHCA (aOR, 0.96 [95% CI, 0.77-1.20]). <h3>Conclusions and Relevance</h3> In this meta-analysis and systematic review, care at high-volume centers was associated with improved survival outcomes, even after adjustment for potential confounders, but was not associated with improved neurological outcomes for patients with nontraumatic OHCA. More studies evaluating the relative importance of center volume compared with other variables (eg, the availability of treatment modalities) associated with survival outcomes in patients with OHCA are required.
Cancer-associated adipose-derived mesenchymal stem cells promote migration and invasion in kidney cancer
Authors: Y. Muto, K. Numakura, Y. Sekine, M. Kobayashi, S. Kashima, R. Yamamoto, A. Koizumi, T. Nara, M. Saito, S. Narita, Y. Omori, T. Habuchi
Journal: European Urology (2022)
Phase II therapeutic equivalence study of Abiraterone Acetate Tablets (I) vs. ZYTIGA<sup>®</sup> in patients with metastatic castration-resistant prostate cancer.
Authors: Dingwei Ye, Xiaojie Bian, Weiqing Han, Bin Wu, Hui Chen, Jitao Wu, Dexin Yu, Huixin Ge, Jian Li, Houbao Huang, Tiwu Fan, Linzhong Cheng, Xiaoping Zhang, Xuepei Zhang, Xin Yao, Junli Wei, Zhenqiang Xu, Peilei Mu, Rong Huang, Huan Wang
Journal: Journal of Clinical Oncology (2022)

e17040 Background: Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the originator abiraterone acetate (ZYTIGA) is observed to be with relatively low bioavailability and high pharmacokinetic variability. Abiraterone Acetate Tablets (I), in which Sodium N-[8-(2-hydroxy-benzoyl) amino] caprylate (SNAC) was added in the formulation as an absorption enhancer, was therefore developed by using nanocrystal technology to enhance the dissolution rate of pharmaceutical compounds, leading to the improvement of the low oral bioavailability and significant food effects. Methods: Patients with mCRPC were randomized (1:1) to receive either Abiraterone Acetate Tablets (I) 300 mg daily plus 5 mg prednisone orally twice daily, or ZYTIGA 1000 mg once daily plus 5 mg prednisone orally twice daily for 84 days. The primary endpoint was serum testosterone concentration (Day 9/10). Secondary endpoints included serum prostate-specific antigen (PSA), pharmacokinetics and adverse events. Results: 68 patients with a median age of 71 (52-84 yrs) (n = 34 in each group) were enrolled in the full analysis set (FAS). The least square geometric mean of Day 9/10 serum testosterone concentration (rounded-up by 1 ng/dl) in Abiraterone Acetate Tablets (I) and ZYTIGA groups was 1.053 (95% CI, 1.006-1.102) and 1.000 (95% CI, 0.956-1.046), respectively. The geometric mean ratio between two groups was 1.053 (90% CI, 0.998-1.110) and the 90% CI fell within 80.0% to 125.0% equivalence limits. The PSA-50 response rate was also similar on Days 28, 56 and 84 (46.9% vs 50.0%, 65.6% vs 57.6%, 71.9% vs 67.7%). Compared with ZYTIGA label, no new safety concerns were observed in Abiraterone Acetate Tablets (I). In addition, Abiraterone Acetate Tablets (I) group was observed to be with lower frequency of treatment-emergent adverse events (TEAEs) of any grade (76.5% vs 85.7%), grade ≥3 TEAEs (8.8% vs 22.9%), and grade ≥3 treatment-related adverse events (TRAEs) (5.9% vs 14.3%). Conclusions: Therapeutic equivalence between Abiraterone Acetate Tablets (I) 300 mg and ZYTIGA 1000 mg was confirmed by Day 9/10 serum testosterone concentration in mCRPC patients. Abiraterone Acetate Tablets (I) also showed a trend of improvement in safety profile. Clinical trial information: NCT04862091.
Reporting consistency in radiation therapy after breast conservative surgery between Arkansas Cancer Registry and all payers claims database.
Authors: Chenghui Li, Sindhu Janarthanam Malapati, Laura Fulper Hutchins
Journal: Journal of Clinical Oncology (2022)

e18685 Background: Cancer registries linked to insurance claims databases are an important source for real-world evidence cancer research. However, most studies used SEER-Medicare linked data, which limits studies by location and age. Arkansas has developed an all-payers claims databases (APCD) that includes insurance claims from both public and private payers, enabling tracking patients of all ages throughout the continuum of care and across payers. However, APCD lacks tumor-specific characteristics. Arkansas is one of only four known states that have linked APCD to the state cancer registry. Using Arkansas APCD linked to Arkansas cancer registry (ACR), we evaluated the reporting consistency of radiation therapy (RT) in the two sources. Methods: We identified women &gt; = 18 years who were diagnosed in 2013-2017 with stage 0-3 hormone receptor positive breast cancer who received breast-conserving surgery. Patients must have continuous insurance coverage (any private plans, Medicaid, Medicare Part A and B without any Part C coverage) in the 13 months (month of diagnosis and 12 months after). Receipt of RT was identified independently from ACR and APCD. ACR collects information on RT if it is part of the first course of therapy. In APCD, RT claims within one year of breast cancer diagnosis were identified using procedure codes. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for receipt of RT coded by the registry compared with APCD billing claims as the gold standard. We assessed the degree of concordance between the data sources by Cohen’s kappa statistic. Results: Of the 2348 patients, 1477 (62.9%) were documented in the ACR as received RT and had RT claims in the APCD, 498 (21%) were documented in the ACR as not received RT and had no RT claims in the APCD, 183 (7.8%) were documented as received RT in ACR but had no RT claims in the APCD, and 190 (8.1%) were documented as not received RT but had RT claims in the APCD. Using APCD claims as the gold standard, the sensitivity, specificity, PPV and NPV were 88.8%, 72.8%, 88.6%, and 73.1%. Findings were very similar using ACR as the gold standard, the sensitivity, specificity, PPV and NPV were 88.6%, 73.1%, 89.0% and 72.4%. The kappa statistic for agreement between the two sources was 0.62 (95% CI: 0.58-0.65, p = 0.7170). Conclusions: In patients who received BCS, recording of RT receipt was moderately consistent between Arkansas APCD and ACR. Future studies are needed to identify factors affecting reporting consistency to better utilize this unique resource in addressing population health problems.[Table: see text]